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Method for inhibiting the replication of herpes virusesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.)Method for inhibiting the replication of herpes viruses description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070004735, Method for inhibiting the replication of herpes viruses. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The invention relates to a method for inhibiting the replication of herpesviruses, to methods for identifying compounds which inhibit the replication of herpesviruses using this method, to compounds having activity against herpesviruses, to methods for their preparation and to their use for producing medicaments for the treatment of herpes infections. [0002] The family of herpesviruses is divided into the three subfamilies of alpha-herpesviruses (e.g. herpes simplex virus of type 1 and 2; HSV1 and HSV2), beta-herpesviruses (e.g. cytomegalovirus; HCMV) and gamma-herpesviruses (e.g. Epstein-Barr virus; EBV). [0003] The manifestations of infections with herpes viruses are, depending on the virus type, disorders of various organs such as the skin, the lymphatic system or the central nervous system. [0004] Infections with the beta-herpesvirus HCMV usually occur during childhood and ordinarily have a subclinical course. The proportion of adults infected worldwide is therefore very high (up to 90%, depending on the investigated population). [0005] Within the family of herpesviruses, cytomegalovirus leads to the highest mortality rate among immunocompromised patients. This is attributable to the fact that cytomegaloviruses cause life-threatening generalized disorders, especially pneumonias, in these people. [0006] HCMV infections in pregnant women may result in serious harm to the child. [0007] The virus particles of herpesviruses have diameters of about 150 to 200 nm and are composed of various structural proteins essential for the virus. The virus core--a fibrillary protein matrix with which the double-stranded linear DNA genome is associated--is located in the interior of the particles. The core is surrounded by an icosahedral capsid which consists of 162 capsomers. The major capsid protein (MCP) of human cytomegalovirus is referred to as UL86. [0008] The viral protein UL80 is processed to at least three different proteins which are involved in capsid maturation. The commonest form thereof is the assembly protein AP. [0009] The formation of virus particles--initially B capsids are formed--is controlled by a precursor complex of UL86 and AP which is responsible for translocation of the MCP (UL86) into the cell nucleus. In the cell nucleus, AP assists the formation of structures which form an internal framework within the B capsids. The viral DNA is packaged into the complete B capsids, with AP being ejected from the virus particles. The DNA-containing infectious virus particles are also referred to as C capsids. [0010] No vaccine for prophylaxis of an HCMV infection is currently available. Ganciclovir is mainly employed for the therapy of HCMV infection but causes serious side effects. [0011] A long-existing need for an improved and, in particular, better-tolerated HCMV therapy emerges from this. The demand for an improved HCMV therapy is moreover enhanced by the fact that firstly organ transplantations are increasingly being performed, and additionally there is a continuous increase in the number of people infected with HIV. Complications arising from HCMV reactivation or HCMV infection are possible in both groups of patients owing to the immunosuppression. There is thus an urgent need for an improved HCMV therapy in these cases. [0012] A preferred object of the present application is to indicate a method with which replication of herpesviruses can be inhibited. This is possible through compounds which are targeted at the major capsid protein and moreover inhibit the formation of C capsids, but not of B capsids. Viruses selected for resistence to this compound show one or more mutations in the gene coding for the major capsid protein. [0013] A further object of the present application is to provide a method for identifying compounds having this novel mechanism of action and having activity against herpesviruses. [0014] This object is achieved by a method characterized in that [0015] a) the major capsid protein or one or more fragments of the major capsid protein is/are brought into contact with test compounds, and [0016] b) the binding of the test substances to the major capsid protein or fragments is measured and [0017] c) the compounds which exhibit binding to the major capsid protein or fragments are selected. [0018] In addition, this object can also be achieved by a method characterized in that [0019] a) herpesviruses are brought into contact with test compounds, [0020] b) resistant herpesviruses are selected, [0021] c) the gene coding for the major capsid protein of these resistant herpesviruses is sequenced, and the resulting protein sequence of the major capsid protein is inferred, [0022] d) the compounds with which resistant herpesviruses having one or more amino acid substitutions in the major capsid protein occur are selected. [0023] A method for selecting compounds having activity against herpesviruses means for the purposes of the present invention a method in which compounds which are novel or are known per se are investigated for their activity against herpesviruses. [0024] In this connection, herpesviruses are, for example, beta-herpesviruses, especially the human cytomegalovirus, especially the HCMV strains Ad169 (ATCC VR-538) or Davis (ATCC VR-807). Use of the strain HCMV-Towne (ATCC VR-977) is not preferred because this already harbors a mutation in the UL86 gene (P1189T) which leads to a corresponding resistance to the substances acting by the mechanism of action described herein. [0025] Surprisingly, test compounds which are distinguished by a unique mechanism of action have been found. On cultivation of HCMV under substance pressure, the formation of B capsids is allowed, whereas the formation of infectious C capsids is prevented. Maintenance of the formation of B capsids during the antiviral treatment might represent an advantage in as much as B capsids initially remain present as immunogen during the viral replication cycle, and this might have advantageous effects, for example in the event of a reinvigorated immune system, for a specific immune defense response resulting therefrom. [0026] In the sequence analysis of cytomegaloviruses resistant to the test compounds, surprisingly only mutations in the capsid protein UL86 were found. [0027] Since these mutated viruses are able to grow under substance pressure, it can be concluded therefrom that the test substance acts precisely on this protein in the sensitive wild-type viruses. Electron microscopic and molecular biology investigations show that the substances inhibit the encapsidation of viral DNA and thus the formation of C capsids. There is no impairment of the replication of the viral DNA and the formation of DNA-free immature capsids (B capsids). Compared with the DNA replication inhibitor ganciclovir which is employed clinically as HCMV medicament, no inhibition of DNA synthesis and expression of the late HCMV genes takes place under the influence of the substances of the invention. The mutations found in UL86 occur preferentially in two regions. The first region extends from amino acid position 435 to 689 and the second region from amino acid position 1189 to 1338 (see Table 2). [0028] The antiviral effect may on the one hand arise through direct interaction of the substance with UL86, or else act via an indirect effect on UL86. [0029] Antiviral substances acting by this novel and surprising mechanism of action can also be obtained by further methods such as, for example, molecular modeling with the aid of the three-dimensional structure of a major capsid protein, molecular modeling on the basis of known UL86 inhibitors etc. These methods are well known to the skilled worker. [0030] Little is known about the functions and interactions of UL86 during capsid maturation and DNA packaging (Wood et al., J. Virol, 1997, 71, 179-190). [0031] The anti-HCMV medicaments currently available are not ideal owing to severe side effects. High-throughput testing of large substance libraries has recently led to inhibitors acting on further viral targets (Wathen, Rev Med Virol, 2002, 12, 167-178). The mechanism of action described herein shows a surprising novel option allowing inhibition of the replication of herpesviruses with the aid of compounds. Continue reading about Method for inhibiting the replication of herpes viruses... Full patent description for Method for inhibiting the replication of herpes viruses Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method for inhibiting the replication of herpes viruses patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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